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HER2/neu antisense targeting of human breast carcinoma
1Department of Surgery, Washington University School of Medicine, Saint Louis, Missouri 63110, USA.
Abstract:
Overexpression of the HER2/neu oncogene is observed in approximately 30% of human breast carcinoma specimens. HER2/neu overexpression is a negative prognostic factor in breast cancer patients. Cancer cells that overexpress HER2/neu may also be less sensitive to chemotherapy. In order to further define mechanisms by which HER2/neu overexpression drives neoplastic cell growth and chemoresistance, antisense oligonucleotides (ODNs) have been utilized to selectively down-regulate HER2/neu expression in human breast cancer cells. Such antisense ODNs suppress HER2/neu mRNA and protein levels in a dose-dependent, sequence-specific manner. Down-regulation of HER2/neu expression in HER2/neu overexpressing breast cancer cells inhibits cell cycle progression in G0/G1 and results in apoptotic cell death. In tissue culture studies, combined treatment of HER2/ neu overexpressing breast cancer cells with HER2/neu antisense ODNs and conventional chemotherapeutic agents results in synergistic inhibition of cancer cell growth and activation of apoptotic cell death mechanisms. These studies have been extended to demonstrate synergistic antitumor effects following systemic treatment with antisense ODNs plus doxorubicin in nude mice bearing human breast carcinoma xenografts. Collectively these findings demonstrate that HER2/neu overexpression stimulates anti-apoptotic cell survival mechanisms and suggest that HER2/neu antisense ODNs may be of use in cancer therapeutics.
Insights
Antisense oligonucleotides targeting HER2/neu oncogene overexpression in breast cancer inhibit tumor growth and enhance chemotherapy effectiveness. This approach shows promise for novel cancer therapeutics by down-regulating HER2/neu and inducing cancer cell death.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- HER2/neu oncogene overexpression is prevalent in breast cancer, correlating with poor prognosis and chemoresistance.
- Understanding HER2/neu's role in tumor growth and resistance is crucial for developing targeted therapies.
Purpose of the Study:
- To investigate the therapeutic potential of antisense oligonucleotides (ODNs) for down-regulating HER2/neu expression in breast cancer.
- To elucidate the mechanisms by which HER2/neu overexpression drives cancer progression and chemoresistance.
Main Methods:
- Utilized antisense ODNs to selectively suppress HER2/neu mRNA and protein levels in human breast cancer cells.
- Assessed the effects of HER2/neu down-regulation on cell cycle progression and apoptosis.
- Evaluated the synergistic effects of antisense ODNs combined with chemotherapy in vitro and in vivo.
Main Results:
- Antisense ODNs effectively reduced HER2/neu expression in a dose- and sequence-dependent manner.
- Down-regulation of HER2/neu inhibited cancer cell proliferation and induced apoptosis.
- Combined treatment with antisense ODNs and chemotherapy demonstrated synergistic antitumor effects in cell culture and xenograft models.
Conclusions:
- HER2/neu overexpression promotes cancer cell survival through anti-apoptotic mechanisms.
- HER2/neu antisense ODNs represent a promising therapeutic strategy for breast cancer, potentially overcoming chemoresistance.
- Systemic administration of antisense ODNs combined with chemotherapy shows significant antitumor activity.